The present invention relates generally to medical devices and products. More specifically the present invention relates to medical devices and products that are coated with a material to provide improved characteristics.
There are literally thousands of products that are used in the medical industry for a variety of treatments and therapies. The surface characteristics of some of these products may be critical to the ability of the products to function. Such products run the gamut from membranes used in blood and cell separation devices, theracyte devices, dialyzers, arterial filters, catheters, wound drains, vascular grafts, and heart valve tissues.
For example, a slippery or low friction surface property is required in various medical devices. These devices include wound drains, chest tubes, guide wires, catheters, and angioplasty products. A lubricious surface is desirable as it reduces pain to the patient during insertion and/or removal of the device.
It is also desirable, on a number of medical products, to provide a surface that has anti-microbial properties. Likewise, medical devices that have surfaces that are non-thrombogenic are valuable in many applications.
In certain applications, it is also desirable to provide a surface that binds to certain type of cells or agents. For example, such products may be desirable for implantable biological tissue such as bioprosthetic valves.
By way of further and more detailed example, in processing whole blood for therapeutic administration to patients, it is desirable to separate the various cellular components. In particular, it is desirable to remove leukocytes because of their role in mediating immunologic reactions which can cause adverse clinical events such as allosensitization. For a review of adverse clinical sequellae to transfusion, see Sekiguchi, et al., Leucocyte-depleted blood products and their clinical usefulness, Ch. 5, pg. 26-33, from The Role of Leucocyte Depletion in Blood Transfusion Practice (1988). Furthermore, leukocytes are unessential for therapeutic supplementation of cell deficiencies in patients involving platelets and red cells. Thus, filter systems have been devised for passaging blood cells in order to remove leukocytes while allowing platelets or red blood to pass through for subsequent recovery.
There have been a number of approaches reported for leukocyte depletion. U.S. Pat. No. 4,330,410 discloses a packed fiber mass with leukodepletion properties comprising fibers of cellulose acetate, acrylonitrile, polyamide, or polyester. U.S. Pat. No. 4,925,572 discloses the use of a gelatin coating to inhibit red blood cell (RBC) and platelet adhesion. Leukodepletion is accomplished primarily through physical entrainment of the cells in the fiber body, and adhesion of RBCs and platelets results from the gelatin coating. U.S. Pat. No. 4,936,998 discloses a strategy for leukodepletion in which a hydrophilic monomer containing hydroxyl or amido groups and functional nitrogen-containing groups such as primary or secondary amino groups is coated onto a filter matrix of known fibers such as polyester, polyamide, etc.
Modification of fiber surfaces has also been used to obtain materials with improved cell separation properties. For example, U.S. Pat. No. 4,130,642 discloses a packed column in which the packing material comprises an Egyptian cotton which has been de-fatted and bleached so that RBC readily pass through the column.
Some separation strategies involve multiple steps. U.S. Pat. No. 4,925,572 discloses a multistep method comprising an upstream porous element for removal of gels, a second element of finer porosity for removal of aggregated matter, and a final filtration step involving common fibers to which surface tension-reducing and improved wetting are obtained by radiation grafting of biocompatible moieties. Further description of leukodepletion methods is contained in Rikumaru, et al., Advanced methods for leucocyte removal by blood filtration, Ch. 6, pgs. 35-40, from The Role of Leucocyte Depletion in Blood Transfusion Practice (1988).
It is of utmost importance in designing leukodepletion strategies in which one goal is to obtain good recoveries of platelets and RBCs, to achieve separations without activating platelets or complement. It is also important that any coatings utilized to enhance the separations not be leached into solution, since the recovered cells are intended for intravascular administration to patients. One approach embodies a filter composed of a porous polymer material with continuous pore structure having a coating combining a nitrogen-containing functional group with a polyethylene oxide chain having 2-15 repeating units (See Jap. Kokai Patent Application No. Hei 5 [1993]-194243). This material is said to entrap leukocytes while giving high yields of platelets.
The use of polyalkylene oxide polymers is well-known in the construction of biocompatible materials, because of its low biological activity in activating cellular and humoral components of blood, and in stimulating immune responses. However, the inertness of the polyalkylene oxide polymers may also interfere with the degree of separation that can be obtained with cell separation filters, unless combined with functional groups that enhance separation parameters. A suitable combination of coating components has not heretofore been developed which is efficacious for cell separations from whole blood as distinct from semi-purified cell suspension mixtures.
Likewise, for a number of other medical products, a suitable material or combination for coating products has not been provided.
The present invention provides improved methods for coating medical products and devices. Additionally, the present invention provides improved coated medical devices and products.
Summarizing briefly, the present invention provides, in an embodiment, medical devices which are coated, at least in part, with a chemical condensation product, prepared by reaction in-situ of a first electrophilically active, high molecular weight polyalkylene oxide, and a second high molecular weight polyalkylene oxide derivative. In an embodiment, the derivative can be either a tetraaminopolyalkylene oxide or a bifunctional dihydroxy- or diamino-polyoxyalkylene derivative, or combination thereof. In another embodiment, the coating may be an isopolymer of a high molecular weight tetraacrylatepolyalkylene oxide, polymerized by exposure to radiation.
The condensation reaction occurs in-situ, e.g. after one polymer is placed onto a surface, the second polymer is then contacted with the surface and specifically the first polymer, and the condensation reaction occurs spontaneously at a temperature between 5 degrees and about 200 degrees centigrade. The electrophilically active, high molecular weight polyalkylene oxide compound has the general structure Y-PEO-R-PEO-Y wherein Y is a reactive moiety selected from an oxycarbonylimidazole, tresyl-, tosyl-, N-hydroxysuccinimidyl, and p-nitrophenyl-activated esters; acrylates; glycidyl ethers; and aldehydes. The oxycarbonylimidazole leaving group is preferred, as will be apparent from the detailed specification, R is a spacer molecule (a chemical backbone) consisting of either bisphenol A (4,4xe2x80x2-(1-methylethylidene)bisphenol) or bisphenol B (4,4xe2x80x2-(1-methylpropylidene)bisphenol), and PEO stands for polyalkylene oxide.
In a method of preparing the material of the present invention, a first polymer comprising an electrophilically active, high molecular weight polyalkylene oxide compound, having terminal leaving groups as indicated herein above, oxycarbonylimidazole being preferred, is applied to the surface, then drying the first polymer onto the surface, followed by applying a second polymer consisting of either a tetraamino-, a diamino-, or a dihydroxy- polyalkylene oxide, or combination thereof. The reaction between the polymers occurs spontaneously, and an incubation at a temperature from about 5 degrees to about 200 degrees Centigrade is continued for a time sufficient to obtain substantial completion of crosslinking.
To this end, in an embodiment, the present invention provides a medical device comprising a body member and a coating on at least a portion of the body member comprising an in-situ condensation product of a first electrophilically active, high molecular weight polyalkylene oxide and a second high molecular weight polyoxyalkylene derivative.
In an embodiment, the portion of the body member is constructed at least in part from polyvinyl chloride.
In an embodiment, the portion of the body is constructed at least in part from silicone.
In an embodiment, the portion of the body is biological tissue.
In an embodiment, the coating provides a lubricious surface.
In an embodiment, the coating includes a third component.
In an embodiment, the coating includes a functional group that modifies the surface.
In an embodiment, the functional group is chosen from the group consisting of anti-coagulants, heparin, hirudin, anti-microbial, proteins, peptides, and biopolymers.
In an embodiment, the coating provides a multilayer structure.
In an embodiment, the coating provides an anti-thrombogenic surface.
In an embodiment, the coating provides a noninflammatory surface.
In an embodiment, the coating provides an anti-bacterial surface.
In another embodiment, the present invention provides a medical device designed to be at least partially inserted into a patient comprising a body member that includes on a portion thereof a coating of a polyalkylene oxide that is cross-linked with a polyalkylene oxide derivative to form a coating that provides a lubricous surface.
In an embodiment, the coating includes water.
In an embodiment, the coating includes a functional group that provides a modified surface property to the coating.
In an embodiment, the device is a catheter.
In an embodiment, the device is a wound drain.
In an embodiment, the device is a guide wire.
In an embodiment, the device is a chest tube.
In an embodiment, the portion thereof is constructed from silicone.
In an embodiment, the portion thereof is constructed from polyvinyl chloride.
In another embodiment, the present invention provides an implantable biological tissue comprising a biological tissue and a coating thereon including a multilayer surface including a high molecular weight polyalkylene oxide derivative and a biopolymer.
In an embodiment, the tissue is a vascular graft.
In an embodiment, the tissue is a heart valve tissue.
In an embodiment, the tissue is a synthetic membrane.
In a still further embodiment, the present invention provides a bioprosthetic device comprising a biological tissue coated at least in part with a coating including a polyalkylene oxide derivative that is cross-linked with a polyalkylene oxide derivative.
Additionally, the present invention provides methods of providing medical devices. In an embodiment, the method comprising the steps of providing a medical device having a body and coating at least a portion of the body with a coating including a polyalkylene oxide derivative cross-linked with polyalkylene oxide derivative to modify the surface properties of the portion of the body.